We hypothesize that novel anti-HIV and anti-STI topical microbicides based on natural antimicrobial peptides collected in the Antimicrobial Peptide Database developed by the co-PI's laboratory (http://aps.unmc.due/AP/main.html) can be discovered and improved through peptide engineering technology. During the R21 phase, we will methodically screen peptides from the database and define specific inhibitors of HIV and HSV-2 as well as broad based inhibitory peptides. These active agents will be further developed in order to understand their range and mechanism of anti-HIV action. Superior peptides identified in SA1 will be characterized in SA2 to provide a rationale for continued development in SA3 using various molecular strategies which will result in the improvement of the therapeutic index of the peptide agents, with and without other small molecule microbicides, in order to begin development of an effective microbicide product. This product will be formulated and evaluated in animal models and safety assessment studies in the R33 portion of the project. Our goal is to produce a female controlled preventative agent which can be utilized to prevent the sexual transmission of viral, bacterial and fungal organisms with a focus on inhibiting the transmission of HIV. The research data will be entered into the existing antimicrobial peptide database to facilitate the use by funding agencies, other researchers, students and the public.